Peripheral distributions of IL-4-producing CD4 + T cells and CD4 + CD25 + FoxP3 + T cells (Tregs) in rheumatoid arthritis patients with poor response to therapy are associated with HLA shared epitope alleles and ACPA status

Specific profiling of CD4?+?T cell subsets in the circulation and inflamed joints of rheumatoid arthritis (RA) patients may have therapeutic implications. This study aimed to evaluate the peripheral distributions of Th2 and Treg cells in relation to HLA-shared epitope (SE) alleles and anti-cyclic citrullinated peptide antibody (ACPAs) status in patients with good response (GR) and poor response (PR) to treatment. The frequencies of IL-4-producing CD4?+?T cells (Th2) and CD4?+?CD25?+?Foxp3?+?T cells (Tregs) were determined by flow cytometry in 167 RA patients including 114 GR and 53 PR cases. CD4?+?T cell subsets were also analyzed based on HLA-SE and ACPAs statuses. One hundred nine of 167 patients were positives for HLA-SE, 63.4% for ACPAs, 43.7% for SE/ACPAs and 14.9% were negatives for SE/ACPAs. Higher frequencies of Th2 (P?=?0.001) and Treg cells (P?=?0.03) were found in the patients versus controls. Increased and decreased frequencies of Th2 and Tregs cells were observed in the PR versus GR patients respectively (P?=?0.003 and P?=?0.004). Higher proportions of Th2 cells were observed in the SE⁺RA versus SE^?RA (P?=?0.001), in ACPA⁺RA versus ACPA^?RA (P?=?0.005) and in the SE⁺ACPA⁺RA versus SE^?ACPA^?RA patients (P?=?0.002). Treg cells frequencies decreased in the SE⁺RA versus SE^?RA (P?=?0.03) and in SE⁺ACPA⁺RA versus SE^?ACPA^?RA (P?=?0.02). ACPA⁺GR and SE⁺PR patients showed higher proportions of Th2 cells than ACPA^?GR and SE^?PR patients respectively (P?=?0.02 and P?=?0.01). Analysis of the CD4?+?T cell subsets profiles in conjunction with genetic background and autoantibodies patterns can be useful for precise therapeutic response monitoring in the RA patients.

     

Relationship Between Perceived Social Support and Psychological Well-Being Among Students Based On Mediating Role of Academic Motivation

The purpose of the present study is to investigate the relationship between perceived social support and psychological well-being among students based on mediating role of academic motivation. Participants were 371 female high school students from second and third-grade students who were randomly selected by applying a multi-stage cluster sampling technique in Tehran, Iran. To examine the research variables, Psychological Well-being Questionnaire of Ryff (1989). Social Support Appraisals Scale of Vaux et al. (1986). and Academic Motivation Measure of Harter (1981) were used. Data analysis was done by calculating correlation coefficients and path analysis. The findings showed that the perceived social support directly and positively influence significant psychological well-being and academic motivation. The path analysis revealed that perceived social support might indirectly have an effect on psychological well-being through mediating role of academic motivation. The perceived social support explained 13 % of the academic motivation variation, and academic motivation predicted 37 % of variation in psychological well-being.     

Two novel GALNT3 mutations in familial tumoral calcinosis

Familial tumoral calcinosis (TC) is characterized by elevated serum phosphate concentrations, normal or elevated 1,25(OH)2 vitamin D, as well as periarticular and vascular calcifications. Recessive mutations in the mucin-like glycosyltransferase GalNAc transferase-3 (GALNT3) and the phosphaturic hormone fibroblast growth factor-23 (FGF23) have been shown to result in TC. In the present study, mutational analyses were performed on two patients with TC to determine the molecular basis of their diseases. Analysis of the first patient revealed a novel, homozygous base insertion (1102_1103insT) in GALNT3 exon 5 that results in a frameshift and premature stop codon (E375X). The second patient had a novel homozygous transition (1460 g>a) in GALNT3 exon 7, which caused a nonsense mutation (W487X). Both mutations are predicted to markedly truncate the mature GALNT3 protein product. Although the patients carry GALNT3 mutations, these individuals presented with low-normal serum concentrations of intact biologically active FGF23 and high levels of C-terminal FGF23. In order to discern a possible relationship between GALNT3 and FGF23 in TC, a comprehensive assessment of the reported TC mutations was also performed. In summary, we have detected novel GALNT3 mutations that result in familial TC, and show that disturbed serum FGF23 concentrations are present in our TC cases as well as in previously reported cases. These studies expand our current genetic understanding of familial TC, and support a pathophysiological association between GALNT3 and FGF23.     

Novel syndrome of cataracts, retinitis pigmentosa, late onset deafness and sperm abnormalities: a new Usher syndrome subtype with X-linked inheritance?

Tissues of the auditory, ocular and reproductive systems have some similarities in their protein families and structures. Consequently, syndromes comprising these systems are described. Hearing loss alone is a component of more than 400 known syndromes and is a common nonsyndromic congenital disorder. Here we describe a syndrome in five brothers with the distinctive presentation of late-onset progressive hearing loss, cataracts, retinitis pigmentosa, sperm motility and shape problems in a family from the Kurdish population in Iran. The clinical findings of these patients are presented in detail and compared to the classical Usher syndromes.     

Indian herbal medicines: possible potent therapeutic agents for rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology and is mainly characterized by the progressive erosion of cartilage leading to chronic polyarthritis and joint distortion. Although the exact pathogenesis of the disease has yet not been elucidated, however, studies suggest that cellular proliferation of synoviocytes result in pannus formation which damages the cartilage and bone. Recent reports also support the role of free radicals in its pathogenesis. Apart from the conventional treatment strategies using nonsteroidal anti-inflammatory drugs, disease modifying antirheumatic drugs and glucocorticoids, newer and safer drugs are continuously being searched, as long term usage of these drugs have resulted in adverse effects. Alternative medicine provides another approach for treatment of RA and currently a number of medicinal plants are under scientific evaluation to develop a novel drug. There is a dire need to investigate the complete therapeutic potential and adverse effects, if any, of these herbals for providing newer and safer treatment options with minimum side effects. In this review we have tried to explore various Indian ancient Ayurvedic, Unani and Tibbi, as also some Chinese and Korean, herbals for their potential to treat RA.     

Evaluation of autoantibodies against vimentin and α-enolase in rheumatoid arthritis patients

IntroductionRheumatoid arthritis (RA) is categorized as an autoimmune disease with a frequency of 0.2–1% worldwide. It is reported that various autoantibodies are produced in the RA population, particularly against citrullinated peptides. Among various candidate markers for RA diagnosis, the citrullinated proteins have the highest specificity and sensitivity for both diagnosis and prognosis of RA. Anti-mutated citrullinated vimentin and α-enolase constitute a new class of autoantibodies for early detection of RA.Material and methods45 serum samples and 19 synovial fluid (SF) specimens collected from RA patients were considered for American College of Rheumatology criteria and 20 serum samples and 10 SF specimens were provided from healthy subjects as a control group. To assess the quantity of anti-citrullinated protein antibodies (ACPA), anti-mutated citrullinated vimentin (MCV) and anti-α-enolase in the serum and SF of RA patients were determined by the enzyme-linked immunosorbent assay (ELISA) method. For the evaluation of disease activity and joint destruction, we used the Disease Activity Score of 28 joints based on erythrocyte sedimentation rate (ESR) Disease Activity Score 28 (DAS28). Furthermore, to measure the molecular weight of vimentin and α-enolase, electrophoresis on 10% SDS-PAGE was performed as described before.ResultsThe anti-α-enolase level among serum samples from RA patients was significantly higher than in healthy subjects (4.49 ±0.20 ng/ml vs. 0.76 ±0.12 ng/ml) (p < 0.001). There was a direct relation between α-enolase quantity and (rheumatoid factor) RF and C-reactive protein (CRP) levels. The mean ESR value in positive and negative ACPA patients was 38.2 ±22.6 mm/h and 9.2 ±5.8 mm/h respectively (p < 0.0001). The mean DAS28-ESR was 3.3. The level of anti-MCV in the serum of RA patients (244.6 ±53.3 U/ml) was higher than in serum of the healthy group (148.73 ±71.8) (p < 0.0001). The level of anti-MCV in the SF of patients was 687.5 ±148.4 U/ml.ConclusionsIn conclusion, both autoantibodies against MCV and α-enolase are two important markers that increase in serum and SF of RA patients and are specific for diagnosis of RA disease.     

The preparation and characterization of novel peptide antagonists to thrombin and factor VIIa and activation of protease-activated receptor 1

Thrombin and protease-activated receptor 1 (PAR1) activation antagonists were prepared based upon the peptide RPPGF, the angiotensin-converting enzyme breakdown product of bradykinin. A library of 72 peptides consisting of d and/or synthetic amino acids was designed with various substitutions in positions 1 to 5 in Arg-Pro-Pro-Gly-Phe (RPPGF). Two compounds, rOicPGF (TH146) and betaAK2K-4(rOicPGF) (MAP4-TH146), were characterized further. TH146 or MAP4-TH146 completely inhibits threshold gamma-thrombin-induced platelet aggregation at a concentration of 142 +/- 0.05 or 19 +/- 0.06 microM, respectively. TH146 completely inhibits threshold alpha-thrombin-induced washed platelet aggregation at 444 +/- 0.04 microM. TH146 or MAP4-TH146 blocks 2 nM alpha-thrombin-induced fibroblast calcium mobilization with an IC(50) value of 110 or 18 microM, respectively. Furthermore, significant prolongation of the activated partial thromboplastin time, prothrombin time, or thrombin clotting time occurs at 31, 62, or 7.8 microM TH146 and 0.4, 6.25, or 1.56 microM MAP4-TH146, respectively. TH146 and MAP4-TH146 inhibit both alpha-thrombin with a K(i) value of 97 and 49 microM, respectively, and factor VIIa with a K(i) value of 44 and 5 microM, respectively. Both TH146 and MAP4-TH146 specifically bind to the exodomain of recombinant PAR1. MAP4-TH146 (200 microM) completely blocks thrombocytin, a PAR1-activating snake venom protease, without inhibiting the enzyme's active site. TH146 inhibits gamma-thrombin-induced aggregation of mouse platelets, prolongs mouse bleeding times, and delays the time to mouse carotid artery thrombosis. TH146 and MAP4-TH146 inhibit human and mouse platelet aggregation and mouse thrombosis. Analogs of RPPGF are model compounds to develop PAR1 activation antagonists as well as direct inhibitors to thrombin and factor VIIa.     

Determination of butyrylcholinesterase (BChE) phenotypes to predict the risk of prolonged apnea in persons receiving succinylcholine in the healthy population of western Iran

OBJECTIVE: The best known clinical application of serum BChE assay is to predict abnormally prolonged apnea following the application of the muscle relaxant succinylcholine. The aim of the present study was to assess the frequency of BChE phenotypes and to predict the risk of apnea for those receiving succinylcholine among the residents in western Iran. METHODS: We examined the frequency of nine BChE phenotypes in 1548 volunteers including 816 males and 732 females with the mean age of 35+/-15 years from an apparently healthy group living in western Iran. The frequencies of BChE phenotypes were determined using BChE activity measurements and by inhibition with dibucaine, fluoride, and the compound Ro2-0683 (Hoffman-La-Roche). RESULTS: The reference range for serum total BChE activity was 4600-14000 U/L (using butyrylthiocholine iodide as substrate). The mean value obtained for men (9030 U/L) was significantly (p<0.05) higher than that for women (8550 U/L). The frequencies of four alleles U, A, F, S were calculated to be 0.9826, 0.0165, 0.008 and 0.001, respectively. The frequency of phenotypes of BChE was as follows: normal phenotype (UU) 95.5%, moderate sensitive to succinylcholine including UA,US,UF phenotypes was 3.9% and hypersensitive to succinylcholine (AA, AF, AS, FF, SS) was 0.58%. CONCLUSION: This study indicates that the population of western Iran has a medium frequency of succinylcholine-sensitive individuals compared to other populations. We suggest that determination of BChE activity and phenotype by the micro automated method is well suited to pre-operative screening and detection of at-risk of prolonged apnea in persons receiving succinylcholine in the healthy population of western Iran.